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YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets

Oncogene volume 29, pages 6160–6171 (2010)Cite this article

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Abstract

Overexpression of the Yes-associated protein (YAP), and TP53 family members ΔNp63 and p73, have been independently detected in subsets of head and neck squamous cell carcinomas (HNSCCs). YAP may serve as a nuclear cofactor with ΔNp63 and p73, but the functional role of YAP and their potential relationship in HNSCCs are unknown. In this study, we show that in a subset of HNSCC lines and tumors, YAP expression is increased but localized in the cytoplasm in association with increased AKT and YAP phosphorylation, and with decreased expression of ΔNp63 and p73. In another subset, YAP expression is decreased but detectable in the nucleus in association with lower AKT and YAP phosphorylation, and with increased ΔNp63 and p73 expression. Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP. ΔNp63 bound to the YAP promoter and suppressed its expression. Transfection of a YAP-serine-127-alanine phosphoacceptor-site mutant or ΔNp63 knockdown significantly increased nuclear YAP and cell death. Conversely, YAP knockdown enhanced cell proliferation, survival, migration and cisplatin chemoresistance. Thus, YAP function as a tumor suppressor may alternatively be dysregulated by AKT phosphorylation at serine-127 and cytoplasmic sequestration, or by transcriptional repression by ΔNp63, in different subsets of HNSCC. AKT and/or ΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs.

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Acknowledgements

We thank Drs Tsutomu Oka, Maie St John and Ms Cindy Clark for their critical review; Ning Yeh, Dr Liesl Nottingham, Dr Jay Friedman, Dr Yansong Bian and Jonah Cohen for technical assistance; and Dr Paul Albert for assistance with statistical analysis. This study was supported by the NIDCD Intramural project Z1ADC-000073, Z1ADC-000074, Head and Neck Cancer Charity Grant and the Breast Cancer Coalition Grant from the Pennsylvania Department of Health.

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  1. Z Chen and C Van Waes: Senior authors.

Authors and Affiliations

  1. Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD, USA

    R Ehsanian, M Brown, H Lu, X P Yang, A Pattatheyil, B Yan, P Duggal, R Chuang, Z Chen & C Van Waes

  2. Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program and NIH-Oxford University/Stanford University School of Medicine, Graduate Partnership Program, National Institutes of Health, Bethesda, MD, USA

    R Ehsanian

  3. NIH-Pfizer Clinical Research Training Program, National Institutes of Health, Bethesda, MD, USA

    M Brown

  4. Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK

    J Doondeea & S Feller

  5. Laboratory of Signal Transduction and Proteomic Profiling at Weis Center for Research, Geisinger Clinic, Danville, PA, USA

    M Sudol

  6. Department of Medicine, Mount Sinai School of Medicine, New York, NY, USA

    M Sudol

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  1. R Ehsanian
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Correspondence to C Van Waes.

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Ehsanian, R., Brown, M., Lu, H. et al. YAP dysregulation by phosphorylation or ΔNp63-mediated gene repression promotes proliferation, survival and migration in head and neck cancer subsets. Oncogene 29, 6160–6171 (2010). https://doi.org/10.1038/onc.2010.339

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